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. 2021 Sep 14;78(11):1097-1110.
doi: 10.1016/j.jacc.2021.07.017.

Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy

Antonio de Marvao  1 , Kathryn A McGurk  2 , Sean L Zheng  3 , Marjola Thanaj  1 , Wenjia Bai  4 , Jinming Duan  5 , Carlo Biffi  6 , Francesco Mazzarotto  7 , Ben Statton  1 , Timothy J W Dawes  8 , Nicolò Savioli  1 , Brian P Halliday  3 , Xiao Xu  3 , Rachel J Buchan  3 , A John Baksi  3 , Marina Quinlan  1 , Paweł Tokarczuk  1 , Upasana Tayal  3 , Catherine Francis  3 , Nicola Whiffin  9 , Pantazis I Theotokis  1 , Xiaolei Zhang  2 , Mikyung Jang  3 , Alaine Berry  1 , Antonis Pantazis  3 , Paul J R Barton  10 , Daniel Rueckert  11 , Sanjay K Prasad  3 , Roddy Walsh  12 , Carolyn Y Ho  13 , Stuart A Cook  14 , James S Ware  15 , Declan P O'Regan  16
Affiliations

Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy

Antonio de Marvao et al. J Am Coll Cardiol. .

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.

Objectives: The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults.

Methods: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.

Results: The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001).

Conclusions: In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.

Keywords: cardiovascular magnetic resonance; deep learning; genetics; hypertrophic cardiomyopathy; penetrance.

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Conflict of interest statement

Funding Support and Author Disclosures This study was supported by the Medical Research Council, UK (MC-A658-5QEB0); the National Institute for Health Research Imperial College Biomedical Research Centre; the National Institute for Health Research Royal Brompton Cardiovascular Biomedical Research Unit; the British Heart Foundation (NH/17/1/32725, RG/19/6/34387, RE/18/4/34215); Fondation Leducq (16 CVD 03); Wellcome Trust (107469/Z/15/Z, 200990/A/16/Z); the National Heart and Lung Institute Foundation; the Royston Centre for Cardiomyopathy Research; Rosetrees and CORDA (Dr Prasad); Academy of Medical Sciences (SGL015/1006; Dr de Marvao); Mason Medical Research Trust grant (Dr de Marvao); SmartHeart EPSRC Programme Grant (EP/P001009/1; Dr Bai and Dr Rueckert); and a Rosetrees and Stoneygate Imperial College Research Fellowship (Dr Whiffin). Dr Ware has consulted for MyoKardia, Inc. and Foresite Labs. Dr Cook holds shares in Enleofen Bio Pte. Ltd. Dr O’Regan has consulted for Bayer AG. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Cardiac Image Analysis in the UK Biobank (A) Machine learning segmentation of the heart from cardiac magnetic resonance imaging (right atrium: light blue; right ventricle: dark blue; left atrium: yellow; left ventricle: red; left ventricular myocardium: green). Motion analysis was used to derive strain and strain rates (radial strain in diastole and systole shown). Regional analysis of left ventricular (LV) wall thickness was performed by using 3-dimensional modeling. Mean wall thickness for 21,322 UK Biobank participants is mapped onto the LV surface; the right ventricle is shown as a mesh. (B) Histogram of maximum LV wall thickness according to sex.
Figure 2
Figure 2
Flowchart of UKBB Participants We included 200,548 participants with whole exome sequencing (WES) in the UK Biobank (UKBB) and stratified them according to variant pathogenicity for outcome analysis. Machine learning was also used to characterize left ventricular traits in 39,551 participants, of whom 21,322 also had sequencing. aIndividuals excluded if carriers of: 1) rare variants in genes associated with HCM genocopies or LV phenotype; 2) intermediate frequency variants (0.00004 < AF < 0.001); 3) variant classes not robustly established as disease causing. bCMRs excluded from WT measure due to nondiagnostic imaging, incomplete sequences, and other technical reasons. AF = allele frequency; CMR = cardiac magnetic resonance imaging; HCM = hypertrophic cardiomyopathy; SARC-HCM-P/LP = pathogenic or likely pathogenic variants for hypertrophic cardiomyopathy in sarcomere-encoding genes; SARC-IND = indeterminate variants in hypertrophic cardiomyopathy–associated sarcomere-encoding genes (rare variants that do not meet criteria for pathogenic/likely pathogenic annotation); SARC-NEG = genotype negative; WT = wall thickness.
Figure 3
Figure 3
Relationship Between Rare Variants in HCM-Associated Genes and WT (A) Dot and boxplots of maximum wall thickness according to genotype. (B and C) 3-dimensional modeling of LV geometry with standardized beta-coefficients showing the strength of association between genotype and regional WT. Contour lines indicate significant regions (P < 0.05) after correction for multiple testing. LV projections are septal (left) and anterior (right). ∗∗∗P ≤ 0.001; ∗∗∗∗P ≤ 0.0001. ns = not significant; other abbreviations as in Figures 1 and 2.
Figure 4
Figure 4
Outcomes Stratified According to Variant Pathogenicity Cumulative hazard curves with zoomed plots for lifetime risk of: (A) death and major adverse cardiovascular events (MACE), consisting of heart failure, arrhythmia, stroke, and cardiac arrest events, or (B) heart failure, stratified according to genotype, consisting of SARC-NEG, SARC-IND, or SARC-HCM-P/LP. (C) Forest plot of comparative lifetime risk of clinical endpoints (Cox proportional hazards models adjusted for sex) according to genotype. Sex refers to male subjects compared with female subjects. Abbreviations as in Figure 2.
Figure 4
Figure 4
Outcomes Stratified According to Variant Pathogenicity Cumulative hazard curves with zoomed plots for lifetime risk of: (A) death and major adverse cardiovascular events (MACE), consisting of heart failure, arrhythmia, stroke, and cardiac arrest events, or (B) heart failure, stratified according to genotype, consisting of SARC-NEG, SARC-IND, or SARC-HCM-P/LP. (C) Forest plot of comparative lifetime risk of clinical endpoints (Cox proportional hazards models adjusted for sex) according to genotype. Sex refers to male subjects compared with female subjects. Abbreviations as in Figure 2.
Figure 4
Figure 4
Outcomes Stratified According to Variant Pathogenicity Cumulative hazard curves with zoomed plots for lifetime risk of: (A) death and major adverse cardiovascular events (MACE), consisting of heart failure, arrhythmia, stroke, and cardiac arrest events, or (B) heart failure, stratified according to genotype, consisting of SARC-NEG, SARC-IND, or SARC-HCM-P/LP. (C) Forest plot of comparative lifetime risk of clinical endpoints (Cox proportional hazards models adjusted for sex) according to genotype. Sex refers to male subjects compared with female subjects. Abbreviations as in Figure 2.
Central Illustration
Central Illustration
Outcomes and Expression of Rare Variants in Hypertrophic Cardiomyopathy–Associated Genes In 200,000 adults, the prevalence of variants pathogenic or likely pathogenic for hypertrophic cardiomyopathy (SARC-HCM-P/LP) was 1 in 407, whereas the aggregate prevalence of indeterminate sarcomeric variants was 1 in 38. The SARC-HCM-P/LP variants were associated with increased risk of death and major adverse cardiovascular events. We found associations with hypertrophic cardiomyopathy–like imaging phenotypes although the prevalence of overt cardiomyopathy was low. SARC-IND = indeterminate variants in hypertrophic cardiomyopathy–associated sarcomere-encoding genes (rare variants that do not meet criteria for pathogenic/likely pathogenic annotation); SARC-NEG = genotype negative.
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